Targeting Langerhans cells using a modular mannosylated nucleic acid-based vaccine platform.

Area of Science:

• Immunology
• Biotechnology
• Materials Science

Background:

• The skin harbors immune cells, including Langerhans cells (LCs) in the epidermis, which are key for antigen presentation and immunotherapy.
• Targeting LCs via their surface receptor, Langerin, with carbohydrate-conjugated therapeutics offers a promising route for vaccination and drug delivery.
• Optimizing carbohydrate-lectin interactions requires precise control over ligand spacing and valency on delivery scaffolds.

Purpose of the Study:

• To design and evaluate a novel nucleic acid-based scaffold for targeted delivery to skin Langerhans cells.
• To investigate the role of scaffold valency and carbohydrate arrangement in enhancing binding to Langerin.
• To assess the efficacy of the scaffold for enhancing antigen presentation and T cell activation.

Main Methods:

• Utilized self-assembled nucleic acid Holliday Junctions as a scaffold, modified for stability and precise carbohydrate arrangement.
• Performed in vitro screening using Langerin-expressing cells and human epidermal cell suspensions to assess binding specificity and valency-driven interactions.
• Evaluated topical delivery on skin explants and antigen-presentation assays with in vitro differentiated LCs.

Main Results:

• Mannosylated Holliday Junction scaffolds demonstrated the strongest binding to Langerin in vitro and in human epidermal cells.
• Specificity and valency-dependent interactions were confirmed, showing effective targeting of epidermal Langerhans cells upon topical administration.
• Scaffolds loaded with mannose and peptide conjugates significantly enhanced T cell activation in antigen-presentation assays.

Conclusions:

• Developed a nuclease-protected, self-assembled nucleic acid platform for precise Langerhans cell targeting.
• Demonstrated valency-driven, specific targeting of LCs via Langerin using mannosylated scaffolds.
• The platform shows significant potential for enhancing skin-directed immunotherapies by improving antigen presentation and T cell activation.